ROLE OF THE BCL 6 PROTO ONCOGENE IN B CELL LYMPHOMAS

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from the investigator's abstract) Aggressive non
Hodgkin's B-cell lymphomas often carry chromosomal translocations in the
proto-oncogene BCL-6 locus. Translocations deregulate BCL-6 expression via
promoter substitution, leading to constitutive high levels of the wild type
BCL-6 protein in lymphoma B cells. In normal B cells, the BCL-6 protein is
expressed only at the germinal center stage. BCL-6 is a zinc finger-containing
transcription repressor. Knock out studies in mice have suggested important
regulatory functions for BCL-6 in the immune system. Still, very little is
known about how its expression is normally regulated in B as well as in non-B
cells. In addition, the mechanism by which abnormal BCL-6 expression
contributes to lymphomagenesis is still unclear. The first specific aim will
attempt to characterize a negative autoregulatory mechanism governing BCL-6
transcription. Experiments are designed to first firmly establish its existence
in B cells with a wild type BCL-6 gene. Its integrity in tumor B cells with
genetically altered BCL-6 gene will then studied. In the second aim, we will
test our hypothesis that continued expression of the BCL-6 protein is essential
for maintaining the tumorigenicity of lymphoma cell lines. We will attempt to
downregulate the activity of BCL-6 protein by expression of either the
antisense or dominant negative BCL-6 mutants (knock down approach).
Corresponding changes in the cellular phenotype of lymphoma cells will be
studied. As our preliminary data suggests a role of BCL-6 in preventing
apoptosis, identifying a link between BCL-6 and apoptosis regulators will be a
priority. In the third aim, effort will be made to search for BCL-6 genes genes
based upon this knock down approach. A combination of cDNA RDA and the cDNA
microarray techniques will be used. The last specific aim is to establish the
causative role of BCL-6 in lymphomagenesis in vivo by generating conditional
BCL-6 transgenic mice using the cre-lox system. Phenotypes to be analyzed
include germinal center enter function, B cell proliferation and tumorigenesis.
StatusFinished
Effective start/end date5/1/004/30/01

Funding

  • National Cancer Institute: $317,057.00

ASJC

  • Molecular Medicine
  • Cancer Research
  • Cell Biology
  • Histology
  • Immunology

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